1. Field of the Invention
The present invention relates to the use of opiate antagonists to treat psychopathologic conditions, more particularly, the use of opiate antagonists to treat emotional numbness associated with Post Traumatic Stress Disorder (PTSD) and other psychopathologic conditions. Emotional numbness is conceptualized as a biopsychological response to extreme emotional or physical trauma.
The present invention also relates to the use of opiate antagonists to treat coma.
2. Description of the Related Prior Art
At this time, there is no pharmacological treatment available for the psychiatric condition of emotional numbing.
The principal feature of emotional numbness is a person's subjective experience of the inability to feel emotions, and is accompanied by a lack of care and concern for self and others. When numbness is profound no feeling can be experienced and the person takes on a "wooden" expressionless and lifeless appearance. Numb individuals are generally unresponsive to the environment and they are socially withdrawn. Unresponsiveness to the environment is a composite disturbance representing a diminished level of mental alertness and awareness and a loss of interest in the outside world. Numb individuals do not experience an empathic bond or a sense of relatedness to others. In social situations they tend to feel alienated and apart. Emotional numbness is frequently associated with numbness and/or paresthesias of the body and feelings of heaviness or paralysis. Severe numbness is accompanied by a profound impairment of concentration and memory with an amnesia for events occurring during the numb state. Information processing of any kind may be severely impaired. When emotional numbness is severe and prolonged, it is usually accompanied by a lack of motivation, interest or pleasure in life's activities. Numb individuals are thus emotionally, mentally, psychologically and socially impaired. They are less able to deal with stresses of any kind -- especially reminders of their past traumatic experiences. They tend, therefore, to avoid thoughts or feelings and activities or situations which might activate recollections of the original traumatic event(s). The one exception to this last statement is the tendency for some numbed individuals to at times actively seek out exciting or (very) dangerous activities in order to overcome their numbness and to experience feeling alive (see below).
The presence of numbing is evaluated clinically as part of the psychiatric diagnosis of PTSD. No independent laboratory tests currently exist to identify the presence or absence of numbing. Numbing (and avoidance) is one of four categories of psychiatric disturbance that must be fulfilled for an individual to receive the diagnosis of PTSD. The American Psychiatric Association's Diagnostic Statistical Manual's (DSMR III-R) definition of numbing (and avoidance) includes seven items, any three of which have to be present for that category (numbing and avoidance) to be fulfilled. Emotional numbness is specifically represented by two of seven items. One item describes the presence of a restricted range of affect, e.g., the inability to have loving feelings. A second item describes a markedly diminished interest in significant activities. Numbing is defined by this Manual as "persistent avoidance of stimuli associated with the trauma or numbing of general responsiveness (not present before the trauma), as indicated by at least three of the following:
(1) efforts to avoid thoughts or feeling associated with the trauma PA1 (2) efforts to avoid activities or situations that arouse recollections of the trauma PA1 (3) inability to recall an important aspect of the trauma (psychogenic amnesia) PA1 (4) markedly diminished interest in significant activities (in young children, loss of recently acquired developmental skills such as toilet training or language skills) PA1 (5) feeling of detachment or estrangement from others PA1 (6) restricted range of affect, e.g., unable to have loving feelings PA1 (7) sense of foreshortened future, e.g., does not expect to have a career, marriage, or children or a long life."
The above conditions are clinical conditions exhibited by an individual which are criteria a health care provider would look to during the psychiatric diagnosis.
Emotional numbing is primarily a subjective complaint. Emotional numbness can vary along three parameters: duration, severity, and social context. Numbness can be experienced for minutes, hours, days, months or years on a continuous or intermittent basis. A person who has severe or profound emotional numbing does not have any feelings at all. In a less severe case, emotions associated with high levels of physiological arousal may be experienced: e.g., rage, fear, and vulnerability. However, tender affectionate feelings are not felt. For periods of time, some less severely numbed individuals may be able to experience love and concern towards a specific individual(s). This may be a child, trusted spouse or fellow survivor of a traumatic episode.
Emotional numbing may be accompanied by a physical experience of heaviness or paralysis of the body, pins and needles, tingling or numbness of parts of the body, feelings of unreality, alienation, and detachment from others. Cognitive disturbances can include mental confusion, amnesia, impaired concentration, indecisiveness, inability to plan future actions, and a paralysis of will. These cognitive disturbances may occur independent of the level of physiological arousal or distress; forgetfulness, disorientation, or confusion can occur without any apparent preceding increase in stress or anxiety.
Some patients are not able to make the distinction between the mental states of numbness and depression. Impaired cognitions, including an absence of self awareness, may interfere with an individual's ability to distinguish between numbness and depression. Other individuals may frequently shift between states of depression and numbness which makes it difficult for them to distinguish their subjective experiences. Numbness and depression also share certain symptoms including impaired concentration and memory and lack of interest and pleasure in life's activities. Emotional numbness should be distinguished from depression. Emotional numbness denotes an absence of feelings (including those of depression and sadness). In contrast to a depressed person, a numbed individual lacks feelings of regard, concern, caring or empathy for himself/herself and others. Common terms which traumatized persons use to describe this numb state of mind include: shutdown, numb, ice cold, hollow, dead, empty and no feelings, care or concern for anyone or anything. Family members commonly regard relations who are numb as being cold, heartless, and emotionally unresponsive. A profoundly numb individual has a wooden facial expression rather than one that is depressed. Very occasionally the emotionally numbed individual may appear to be angry or sad to others, yet respond with bewilderment or denial when questioned about his/her look of anger or sadness.
Numbed persons may learn to role play appropriate behavioral responses in family and social settings even though they continue to have no feelings. When questioned, these individuals may relate what they thought they should have felt based on their inferences and judgments about the situation rather than what they actually experienced.
The mental state of emotional numbness is a disabling condition for the traumatized victim and his or her family members. Numbness interferes with a person's ability to enjoy and participate in life's activities (work, intimacy, sex, etc.) and with the individual's ability to respond with genuine affection, interest or concern about anybody or anything, which can oftentimes lead to marital and family discord. Although a numbed individual may be less likely to respond emotionally to most situations, the same individual may be more likely to lash out than to exercise restraint once enraged because of his/her indifference to the consequences of his/her actions. In addition, rage can also precipitate or intensify the numb response.
When numbed individuals do experience negative emotions such as rage, bitterness, hostility or betrayal, these mood states continue for extended periods of time. However, emotions that are positively felt decay rapidly and evaporate.
Some individuals with emotional numbing may seek out sensation and risk-taking activities such as skydiving, racing cars, gambling, drug abuse, self-inflicted pain, etc. in an effort to escape the deadening effect of numbness. These activities can assume a compelling addictive drive accompanied by intense feelings of craving.
Endogeneous opiates (endorphins) are actively produced in the central nervous system (CNS) in response to stress. Endorphins represent one of the primarily major inhibitory neurotransmitter systems, inhibiting the release of other neurotransmitters, both in the CNS and in the peripheral organs. Endorphins can inhibit the neural transmission of sensory information in the spinal cord. Endorphins have been strongly implicated in the experimental paradigm of stress induced analgesia. Conditioned stress induced analgesia is believed to be specifically endorphin dependent.
Exogenous opiates demonstrate a variety of effects on the mood and behavior of animals and man depending on dose, chronicity, method, site and timing of administration (in relation to exposure to stress). Responses may vary from calm sedation and euphoria to dysphoria and agitation. Opiates are well known for their ability to cause mental confusion, apathy and reduction of anxiety associated with pain.
The limbic system of the CNS is where emotions, motivations and interests are processed and modulated. It is a region densely populated with opiate receptors. In PTSD endorphins are postulated to shut down the processing of emotional experiences and motivational systems which leads to numbness and loss of interest.
The hippocampus is a structure within the limbic system which is considered important for memory processing, including the consolidation and establishment of long term memory. Amnesia is classically associated with damage to the medial temporal brain region, especially the hippocamus formation. This region, in turn, has extensive projections to specific sensory modality pathways and polymodal areas in the neocortex where long term memory storage probably occurs. These areas are also densely occupied by opiate receptors. Opiates have also been found to be capable of inducing amnesia in experimental animals. Excessive secretion of endorphins in these regions are hypothesized to lead to symptoms of mental confusion, disorientation and amnesia.
States of numbness are similarly postulated to occur in other psychopathological conditions. These include affective disorders such as "masked" depression and severe or psychotic depression. The latter condition is generally unresponsive to antidepressants but is responsive to electric shock therapy. Opiate antagonist medication provides an alternative to that form of intervention for many of these individuals. A number of psychological and clinical states may produce apathy which, by definition, includes the absence of emotions. When apathy is not the result of organic degeneration of the central nervous system it should similarly be considered for opiate antagonist treatment. Severely anxious individuals and those with hypochondriacal and psychosomatic conditions may experience numbness. Alexithymia, a condition in which individuals are unable to describe their feelings verbally, is observed in persons with the diagnosis of PTSD and in persons with psychosomatic disorders. It is postulated that a percentage of individuals with alexithymia manifest this difficulty as a result of emotional numbness. Furthermore, schizophrenic conditions in which negative symptoms including apathy predominate also experience emotional numbness. In all these conditions, numbness represents an extreme biopsychological response to the stress of emotional overload so that the emotional experience is profoundly dampened down or turned off and the expenditure of metabolic energy is reduced. The numb state, however, creates additional problems of its own (as described above). Numbness can become the principal response to any nonspecific situation in which an individual feels vulnerable and/or unable to cope. This is especially true of the PTSD population, where the numb response is likely to become a chronic and persistent problem.
Nalmefene is a known narcotic antagonist.
U.S. Pat. Nos. 3,814,768 and 3,896,226 both to Fishman disclose nalmefene and its pharmaceutically acceptable salts per se and as a component in narcotic antagonist compositions, respectively.
Compounds related to nalmefene, i.e., having the same pentacyclic nucleus, including naloxone, naltrexone, nalbuphine, thebaine, etc., are also known and are used to treat mental illness.
U.S. Pat. No. 4,388,324 to Horrobin discloses the use of certain opiate antagonists, e.g., naloxone to enhance the prostaglandin (seris 1) levels which are suggested to thereby indirectly influence schizophrenia and depression.
U.S. Pat. No. 3,717,643 to Archer discloses the use of certain morphine derivatives as central nervous system stimulants. U.S. Pat. No. 3,299,072 to Bartels-Keith discloses the use of certain thebaine derivatives for the same purpose.
U.S. Pat. No. 3,282,050 to Buckett et al. discloses the use of certain morphine derivatives as tranquilizers or psychosedatives.
U.S. Pat. Nos. 4,154,142 and 4,511,570 disclose the use of a particular normorphone derivative to treat hyperkinetic children and senile adults, respectively.